1. Field of the Invention
A pharmaceutical composition is provided for a medicament which is sensitive to a low pH environment of less than 3, such as pravastatin. Novel, stable oral dosage formulations of pravastatin are provided which include a buffering agent to stabilize and maintain the pH below 9 in an aqueous dispersion. As used in this application, the term pravastatin refers to the free base form of the drug as well as the pharmaceutically acceptable salts such as pravastatin sodium.
2. Description of the Related Art
Pravastatin sodium, designated chemically as [1S-[1α (βS*,δS*), 2α, 6α, 8β-(R*),8aα]]-1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid monosodium salt is a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor antilipemic agent described in U.S. Pat. No. 4,346,227. It is indicated in hypercholesterolemic patients for primary prevention of coronary events including myocardial infarction (MI); to reduce the risk of undergoing myocardial revascularization procedures; to reduce the risk of cardiovascular mortality. It is indicated in hypercholesterolemic patients for secondary prevention of cardiovascular events, including MI and to slow the progression of coronary arteriosclerosis. Pravastatin is also used as an adjunct to diet for the reduction of elevated total- and LDL-cholesterol and triglyceride levels in patients with primary hypercholesterolemia and mixed dyslipidemia (Types IIa and IIb). The agent specifically competitively inhibits 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, which is an early rate-limiting step in cholesterol biosynthesis. HMG-CoA reductase inhibitors increase HDL cholesterol and decrease LDL cholesterol, VLDL and plasma triglycerides. The usual dosing regimen is 10-40 mg once daily at bedtime.
Certain drugs require an alkaline environment for the purposes of stability. Stability requirements are covered in the United States Pharmacopoeia (U.S.P.), in the Good Manufacturing Practices (GMPs) as well as in FDA Guidelines for stability studies. Buffers may be added to increase stability of certain pharmaceuticals. Buffers may also increase the thermo stability of drug in formulations that require drying during the process of producing the final dosage form.
Pravastatin sodium is relatively polar hydrophilic, acid labile, and degrades to form its lactone and various isomers. Degradation results in lower bioavailability of pravastatin sodium. Pravastatin sodium requires a buffer to enhance storage stability. Strategies used in the prior art to stabilize pravastatin sodium formulations include: addition of a basifying agent to raise the pH to at least 9, and packaging of the product in a manner to decrease exposure to moisture.
The stability of pravastatin sodium is affected by factors including formulation and storage conditions. Pravastatin sodium is known to be an acid labile compound. Labeling of pravastatin sodium tablets indicates storage at a temperature not to exceed 30° C. and protection from light and moisture.
Stabilization is achieved by basification of the environment in which degradation occurs. Stabilized compositions in the prior art have a pH of 9 or over in an aqueous dispersion. The amounts of basifying agent range from 1 to 75%. Basifying agents used include magnesium oxide. Patents such as U.S. Pat. Nos. 5,180,589, 6,235,311, 5,225,202, 5,030,447 (which are incorporated herein by reference) describe aluminum oxide, all alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide, or alkaline earth metal hydroxides such as calcium, magnesium, aluminum hydroxide, dihydroaluminum sodium carbonate, aluminum magnesium hydroxide sulfate, aluminum hydroxide magnesium carbonate co-dried gel, or ammonium hydroxides, calcium carbonate, magnesium carbonate, magnesium stearate, piperazine, sodium acetate, sodium citrate, sodium tartrate, sodium maleate, sodium succinate and mixtures thereof. Stabilization of the commercially available pravastatin sodium (Pravacol®) is achieved by basification by magnesium oxide which imparts a pH above 9, preferably about 10.
Although the prior art basifying agents can prevent the degradation of pravastatin sodium, they are less desirable because some are strong bases which may have an adverse effect on excipients used with pravastatin sodium pharmaceutical compositions. For example, lactose discolors and emits a caramelized odor in the presence of certain basifying agents, for example piperazine. Additionally, the high alkalinity occurring at dissolution of these formulations may disrupt the acidic pH milieu of the gastrointestinal (GI) mucosa and is problematic for patients with pre-existing GI mucosal damage.
The need exists for a stable pravastatin formulation prepared from an aqueous dispersion of hydrophobic polymers. Such formulations have a practical application, and represent a valuable contribution to the medical arts. The present invention provides such compositions, and offers efficient and cost effective methods of preparation.